Parkinson's disease (PD) has a prevalence of 1-2% worldwide in people over the age of 50. PD results from the death of dopamine-producing cells in the substantia nigra pars compacta (SN), a small region of the brain. Dopamine is required to control movement and low levels of dopamine result in the typical symptoms of Parkinson's - tremor, slowness of voluntary movement, muscle stiffness or rigidity, shuffling gait, loss of balance, slurred speech and increasing dependence on others. Existing therapies are not satisfactory. Gene therapy holds promise, but focal delivery of DNA and the level of gene expression are challenging problems. Macrophages are recruited from bone marrow to most tissues of the body including the CNS, thus making them an attractive option for gene delivery. Galactosialidosis (GS) has been corrected by bone marrow-derived macrophages expressing human protective protein/cathepsin A (PPCA) transgene in a mouse model (PPCA-/-). However, correction in the CNS was incomplete due in part to weakness of the CSF-1R promoter used in the study. We have developed a series of super macrophage promoters (SMP) that are up to 100-fold stronger in vitro than the CSF-1R promoter. In PD patients and model animals, local delivery of glial cell line-derived neurotrophic factor (GDNF) has been found beneficial. We hypothesize that highly effective CNS delivery of GDNF can be achieved with the use of our super macrophage promoters and this will provide dopamine neuron protection in animal models of PD. Our specific aim is to ameliorate neurodegeneration in the MPTP (1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease by syngeneic transplantation of HSC transduced ex vivo with lentivectors expressing GDNF gene in macrophages/macroglia driven by the SMP. Bone marrow stem cells will be transduced ex vivo with GDNF expressing lentivirus and transplanted into lethally irradiated recipient mice. Five weeks after bone marrow transplantation, the recipient mice will be subject to either acute or chronic MPTP treatment. At selected time points post MPTP, behavioral testing will be performed, and brain tissue will be examined for dopamine uptake and expression of tyrosine hydroxylase (TH). Dopaminergic neurons will be counted and cell apoptosis will be assessed by TUNEL staining and immunohistochemistry for active caspase-3. The study will serve as a basis for developing vectors for potential use in patients with neurodegenerative diseases.